Identifying the young patient at
risk of malignant arrhythmias and sudden cardiac death remains a
challenge. It is increasingly recognised that sudden death, syncope and
aborted cardiac arrest at a young age in patients with a structurally
normal heart may be the result of various ion channel disorders - the
channelopathies. The approach to risk stratification involves a
combination of the clinical presentation, taken in conjunction with the
family history, genetic testing, invasive electrophysiological studies
or other provocative tests where appropriate and feasible. A logical
approach to risk stratification in some of the commoner channelopathies
seen in paediatric practice is presented.

Key words:Channelopathies;
Risk Stratification

Introduction

The recognition that several of the common causes of sudden
arrhythmic death in young patients are the result of mutations
affecting ion channels at the level of the individual cell (and hence
the generic disease description of channelopathies) has led to
increasing interest in genotyping. For clinical practice, it is of
interest to investigate to what extent genotyping is of relevance in
the management of an individual patient suspected or known to have a
channelopathy, and to compare the results of such genetic testing with
the use of clinical markers of risk for sudden death. We will provide a
brief overview of the commoner symptomatic channelopathies which
present in young patients.

The congenital long QT syndrome

Since its initial clinical description, our knowledge of the disease
entity, the cellular mechanisms that underlie the various forms of the
disease (the number of different genotypes associated with the long QT
syndrome is currently 12) and the association between specific
genotypes and the risk of sudden death has expanded exponentially. The
relationship between genotype and phenotype (the clinical expression of
the disease) has been well studied. Initial studies focused on the
specific ECG characteristics of the three commonest genotypes (LQTS
types 1-3) which account for approximately 70% of patients with the
long QT syndrome. Particularly in adult patients, the QT morphology was
shown to be quite distinctive for each of these genotypes, although
there are substantial variations in repolarization abnormalities
observed in the same subject and in members of the same family
indicating both the dynamic nature of the disease and differences in
gene penetrance [1-4]. Such relative specificity has also been observed
for triggers for cardiac events (syncope or sudden cardiac death)
and the clinical course (age at onset of cardiac events and risk for
aborted cardiac arrest or sudden cardiac death). In studies of genotype
- phenotype correlation, it has been shown that arrhythmias were
triggered primarily by exercise or emotional upset in LQTS1, by
emotional upset and particularly sudden auditory stimuli in LQTS2,
while arrhythmia occurred primarily at rest or during sleep in LQTS3
[5-7]. Swimming was found to be a particularly important trigger for
ventricular arrhythmia in LQTS1 [6,8,9]. The genotype has also been
demonstrated to be important in determining the incidence of cardiac
events, from early studies arising from the international LQTS registry
[10]. The risk of cardiac events has been shown to be significantly
higher in LQTS 1 and LQTS2 when compared with LQTS3, with events
occurring at a younger age. The cumulative mortality however was
similar regardless of the genotype, as patients with LQTS3 had a higher
percentage of potentially lethal events [10]. As will be seen, these
early findings have to a large extent been reconfirmed by follow-up
studies of the different age categories of patients in the LQTS
registry.

Genotyping to
assess risk of sudden death

Knowing the specific mutation, or the location of the mutation has been
shown to improve risk stratification. For LQTS 1, Shimizu et al
demonstrated mutation site-specific differences in the risk of lethal
arrhythmia in a Japanese population [11]. They showed that patients
with mutations in the transmembrane domain of the KCNQ1 ion channel had
more frequent cardiac events (syncope, aborted cardiac arrest or sudden
cardiac death) than patients with C-terminal mutations. They also had a
greater risk of the first cardiac event occurring at a younger age.
Several baseline ECG parameters affecting cardiac repolarization
(Q-Tend, Q-Tpeak, Tpeak-end intervals) were also significantly longer
in subjects with transmembrane mutations, with exaggerated response of
some of these measures (Q-Tend and Tpeak-end) to sympathetic
stimulation. The differences in the dynamic response of ventricular
repolarization to sympathetic stimulation between the 3 main genotypes
(LQT1 to 3) had already been previously established by Noda et al, who
showed that the QTc was maximally prolonged as the RR interval
decreased in LQTS1 patients, moderately prolonged in LQTS2 patients,
and least prolonged in LQTS3 patients in response to intravenous
epinephrine [12]. They speculated, justifiably, that this difference in
the dynamic response of ventricular repolarization to sympathetic
stimulation may explain why the trigger for cardiac events differs
between the genotypes. Moss et al demonstrated that patients with
transmembrane mutations were at increased risk of cardiac events
compared with those with C-terminus mutations. In addition, the
biophysical function of the mutation was also important in determining
the phenotype. Patients with a dominant negative effect of the mutation
on ion channel function (>50% reduction in function) had a more
severe phenotype compared with those exhibiting haploinsufficiency
(< or = 50% reduction in IKs potassium channel current) [13].
These genetic risks were independent of traditional clinical risk
factors such as the manifest QTc interval on the ECG, suggesting that
variability in the electrophysiologic effects of the different
mutations contributes to the variability in the risk of
life-threatening cardiac events [14]. This in turn suggests that it is
not sufficient to know the genotype, but knowledge of the specific
mutation and its biophysical function is essential for risk
stratification. For LQTS2, similar genotype-phenotype correlations have
been established. It has been shown that subjects harbouring pore
mutations have a more severe clinical course and a higher frequency of
arrhythmic events occurring at a younger age when compared with those
with nonpore mutations [15]. In a more recent study, missense mutations
in the transmembrane pore (S5-loop-S6) region were associated with the
highest risk of clinical arrhythmia [16]. Further studies involving the
US, Japanese and Netherlands LQTS registries are currently underway to
further analyse risk associated with specific mutations in the HERG
gene. Preliminary data for LQTS3 subjects with SCN5A sodium
channel mutations also suggest that the location of the mutation and
its biophysical function may be important determinants of the clinical
phenotype [17-19], although further data from the combined LQTS
registries are awaited.

Even more interestingly, and further supporting the case for detailed
genetic studies as part of the diagnostic work-up in assessing risk, it
has been shown that specific mutations are associated with unusual
clinical severity. The KCNQ1-A341V mutation was shown in a founder
population in South Africa to have a severe phenotype [20]. While the
QTc (if >500 ms) also affected the phenotypic expression, when
matched for QTc with LQT1 database patients, the presence of a KCNQ1-
A341V mutation was still associated with a larger probability of
experiencing a cardiac event. Additional studies on subjects from
different ethnic backgrounds have confirmed the unusual clinical
severity associated with the KCNQ1-A341V mutation, suggesting that
mutation-specific behaviour exists independent of ethnic or genetic
background. The KCNQ1-A341V mutation carriers were more likely to have
cardiac events at a younger age, and also had a longer QTc [21].
Given the wide variations in QTc in individuals carrying the same
mutation, it is also evident that additional genetic or environmental
influences play a role in modifying both the QTc and the risk of sudden
death. A lower resting heart rate has been shown to be protective,
suggesting that individual autonomic make-up modulates phenotypic
expression [22,23]. Whether a blunting of the autonomic response in
individual subjects (conferring a protective effect) may be affected by
specific adrenergic gene receptor polymorphisms has been the subject of
subsequent investigations [23]. The clinical phenotype is not
completely explained by the electrophysiologic effects or biophysical
properties of the mutation, which has been shown to have a dominant
negative effect on IKs. In the absence of detailed information on
possible modifier genes, identification of the specific mutation alone
is therefore insufficient in predicting individual risk. Other modifier
genes which affect the severity of clinical expression of LQTS have
been subsequently identified. These may vary from coinheritance of two
independent mutations, either of which when inherited alone have a mild
phenotype but when present in combination produce severe clinical
manifestations [24], to the association of LQTS mutations with certain
single nucleotide polymorphisms, occurring with varying degrees of
frequency in the general population but which in combination produce a
severe clinical phenotype [25-27].

Specific single nucleotide polymorphisms, often occurring commonly in
specific populations, have also been associated with a higher incidence
of arrhythmic events and sudden death. The S1103Y polymorphism in the
SCN5A gene is present in between 10 to 13% of healthy African
Americans, and is the result of a single nucleotide substitution of a
cytosine (c) for an alanine (a) in the second position of codon 1103,
resulting in an amino acid change (serine for tyrosine in amino acid
position 1103). It is associated with a markedly increased risk of
arrhythmias in unrelated African American adults with arrhythmias [28],
with QTc prolongation and syncope, and with an eightfold increase in
the risk for sudden arrhythmic death in young African Americans [29].
It is also overrepresented in the sudden infant death syndrome, and in
autopsy-negative sudden unexplained death in subjects older than 1 year
in this specific population [30,31].

To summarise, the established yield of genetic testing in clinically
irrefutable cases of LQTS is high [32]. There remains however, a
considerable chance that a positive genetic test is a false
positive, and this is to some extent ethnicity dependent. In turn, this
also means that as the clinical probability of LQTS decreases the
probability that an identified mutation is non-causative
correspondingly increases [33]. The nature of the mutation (nonsense,
frameshift, splice-mutations or missense mutations) and the location of
the mutation will all affect pathogenicity. The role of additional
modifier genes in determining phenotypic expression in different
individuals with an identical mutation also needs further elucidation.

Clinical risk
stratification in the LQTS

Several studies in the different age categories have been made possible
by the establishment of various LQTS registries. This has in turn made
possible risk assessment for SCD/ACA (sudden cardiac death/aborted
cardiac arrest) events based on several clinical
and ECG criteria. Some of these will now be briefly described.

The risk factors for a cardiac event during the first 12 months of life
(SCD/ACA/syncope) include a QTc ≥ 500, a resting heart rate of ≤ 100
beats/minute, and female sex. The risk for a subsequent SCD/ACA remains
high, as established during a 10 year follow-up of this subset of
patients, and beta-blocker therapy is only partially protective [34].
This has also been borne out by observations in other studies with
shorter duration of follow-up [35]. Bradyarrhythmia (sinus bradycardia
or functional 2:1 AV block) are also common in this population [36].
Long QT syndrome patients who experience potentially lethal clinical
events in the first year of life are at high risk for similar events in
the first decade of life, and additional therapies such as permanent
pacing, left cardiac sympathetic denervation or early implantation of a
defibrillator need to be considered on an individual basis. There is
also an association between long QT syndrome and sudden infant death
syndrome (SIDS), and routine newborn ECG screening has been advocated
to identify infants at risk [37]. A detailed description of the risks
and benefits of such an approach are beyond the scope of this review,
but may be found in the following reviews [38,39]. It is to be
anticipated however that routine ECG screening of siblings and other
close family members of the index patient presenting in infancy will be
more routinely undertaken, resulting in early identification of
potentially affected, but as yet asymptomatic, individuals. Whether
early institution of beta blocker therapy in individuals thus
identified will be protective, is at present unknown. Sudden death of a
sibling (at any age) has been thought to be associated with a higher
risk of death in the LQTS population. This has however not been
confirmed in an LQTS registry study of first- and second-degree
relatives of probands. Sibling death was not significantly associated
with increased risk of SCD/ACA; instead, the risk of adverse
events in relatives was determined more by individual risk factors
which included a QTc ≥530, a history of syncope, and gender [40]. QTc
was highly predictive of ACA/SCD. A personal history of syncope,
particularly if syncope had occurred within 2 years, was also strongly
associated with ACA/ death. The effect of gender was time-dependent.
The risk of ACA/death/any cardiac event was higher in boys than in
girls at a young age, but this relationship changed from late
adolescence onwards, when women had a higher risk than men [40]. To
conclude, severe symptoms in a close relative cannot be used as an
indicator of personal risk for other family members who may have the
same genotype, although such subjects are more likely to be treated
with beta blockers from a young age [40].

In children aged 1 to 12 years, boys were at a significantly increased
risk of ACA/SCD. The risk factors for boys included a QTc>500 and
prior syncope (with recent syncope within the previous 2 years carrying
a higher risk) whereas prior syncope (recent syncope being more risky
than remote syncope) was the only significant risk factor in girls
[41]. Routine beta blocker therapy was clearly protective, and was
associated with a significant reduction in the risk of life-threatening
cardiac events in this age group. Regardless of genotype, a family
history of SCD did not predict a higher risk of cardiac events in
childhood. Similar considerations apply to the adolescent population
(aged between 10 and 20 years). Syncope (both timing of syncope and
number of syncopal events) was a significant risk factor for predicting
ACA/SCD, with recent (within the last 2 years) syncope and higher
number of syncopal events during this period carrying a higher risk
[38]. A QTc ≥530 was associated with increased risk. The effect of
gender was age-dependent, with boys at higher risk in the age category
10-12 years, and no significant difference in gender-related risk being
observed between 13 and 20 years [42]. The predominance of
life-threatening events in boys during childhood and early adolescence
may be the result of environmental (increased sport participation/
intensive physical activity), hormonal (opposing effects of estrogens
and androgens on ventricular repolarization) or genetic (modifier genes
not shared by boys and girls) influences [42]. Data on the specific
genotype (LQTS1 vs LQTS2 vs LQTS3) did not contribute significantly to
the outcome, as syncope was not used as one of the cardiac end-points
unlike previous genotype based studies, but rather as a time-dependent
covariate to assess the end points of ACA/SCD [10,42].

Beyond 40 years of age, women with a QTc ≥470 are at
a higher risk of SCD/ACA, while in men event rates were similar in the
various QTc categories unaffected (QTc<449), borderline (QTc 440 to
469) and electrocardiographically affected (QTc ≥470). Recent (<2
years in the past) syncope was the predominant risk factor in affected
subjects, and those with a positive mutation had a significantly higher
mortality, particularly those with an LQT3 mutation [43]. After the age
of 60 years, the risk of death due to LQTS competes with other disease
entities which may lead to death. Even in this older population, a
trend towards lower mortality was observed in patients treated with
beta blockers, although this may have been the result of multiple
protective mechanisms. Timely ICD implantation should obviously be
considered in high risk patients remaining symptomatic despite beta
blocker treatment.

The long QT
syndrome in patients with other
phenotypic anomalies

Patients with associated phenotypic manifestations (Jervell and
Lange-Nielsen syndrome in its homozygous or compound heterozygous state
and associated with sensorineural deafness, Timothy syndrome which
manifests skeletal abnormalities, syndactyly, structural heart disease,
autism and immune deficiency with predisposition to sepsis usually have
more severe clinical forms of the congenital long QT syndrome.
Especially with the J and L-N and Timothy syndromes, they are also less
likely to respond to beta blocker therapy alone, and early
defibrillator implantation appears to be mandated in this population
[44,45]. The QTc (if ≥550) and a history of syncope during the first
year of life appear to be predictive of the degree of risk in
individual patients with the Jervell and Lange-Nielsen syndrome
[44,46]. In contrast, the Anderson-Tawil syndrome which may be
associated with dysmorphic features, periodic paralysis and propensity
for ventricular arrhythmias (PVCs and bidirectional ventricular
tachycardia rather than torsade de pointes), has a generally more
benign clinical course in terms of arrhythmic death [47]. The majority
of these syndromes may be suspected from the presence of these
characteristic clinical findings, and appropriate therapy decided upon.

Do we need to
know the genotype when selecting therapy?

The arguments against routine genotyping for risk stratification and
for selecting therapy in patients with long QT syndrome can be made on
several grounds [48]. As seen above, clinical risk stratification is
quite effective, when one considers the clinical presentation
(syncope/ACA versus no symptoms) in combination with the QTc (if
>500) [49,50]. The demographics of LQTS have also changed
remarkably, with increased awareness of the disease and consequent
early diagnosis. Unlike the view held prior to genotyping and the
establishment of genotype-phenotype correlations, LQTS is associated
with a low rate of SCD/ACA, and the majority of patients are
asymptomatic carriers. A significant proportion of phenotypically
affected patients and their families cannot be identified at present by
genetic screening alone, and given the varied clinical expression of
symptoms (and QTc) in different family members carrying the same
genetic mutation, therapy and clinical risk stratification cannot be
standardised based on the identification of a specific mutation. Most
importantly, there are only a limited number of therapies available
which may prevent sudden arrhythmic death (beta blockers, ICD
implantation, and probably selective left cardiac sympathetic
denervation). Beta blockers have been shown to be highly effective
(given appropriate patient compliance) for LQTS 1 and LQTS2, and for
the subset of LQTS3 patients who have clinical events mediated by
excessive adrenergic stimulation [51]. It seems reasonable therefore to
recommend routine beta blocker therapy in all patients with the
clinical diagnosis of LQTS, without knowledge of the genotype. The
majority of LQTS3 patients (who form a small subset of the entire LQTS
population) without adrenergic mediated events remain asymptomatic well
into adult life, and perhaps do not require routine prophylactic
therapy. The ICD may therefore be reserved for patients with persistent
symptoms (recurrent syncope) despite beta blocker therapy, and those
presenting with ACA. Data from children obtained in the era of ICD
implantation tend to confirm these observations [50]. Early
identification of the disease and appropriate beta blocker therapy in
combination with necessary physical restrictions and avoidance of QT
prolonging medications (comprehensive lists of such drugs may be found
on several websites such as www.azcert.org and www.Torsades.org) may
all play a role in reducing mortality. Efficacy of beta blockade may
require additional investigations such as exercise testing or
epinephrine challenge [53,54]. There are even data suggesting that the
differential response to epinephrine provocation helps to distinguish
between the three major LQTS genotypes, allowing the application of
presumptive genotype-specific treatment strategies [55]. While the
current clinical practice tends to favour ICD implantation in young
patients with a proven LQTS3 genotype, there is no evidence at present
that this aggressive approach is warranted if the majority of LQTS3
patients remain asymptomatic well into their 40s.

The Brugada syndrome in paediatric
practice

Risk stratification in adults with the Brugada syndrome has been
extensively investigated [56-60]. In contrast, risk stratification in
children is hampered by several factors. The disease is rare in large
segments of the world's population; it often does not manifest
clinically in childhood, and in the absence of a positive family
history, identification of the index case in childhood can be
difficult. Genetic testing provides a positive result in only
approximately 30% of patients with the clinical phenotype of Brugada
syndrome. While the ajmaline (or flecainide) tests have been used to
identify patients who might have Brugada syndrome, a positive test does
not predict the risk of future clinical events, and routine testing in
childhood in asymptomatic individuals has generally not found favour,
except in instances where there is an adverse family history and a
negative genetic study, and where the parents are anxious to know
whether their offspring has the disease [61,62]. Finally, therapeutic
options, even after confirmation of the clinical phenotype by
provocative tests, are limited.

Data on Brugada syndrome in children, apart from small case series or
single reports are predominantly limited to a single multicenter study
[63,64]. Thirty children aged <16 years were identified from 13
participating centers. All of them had a type 1 ECG either at rest or
following drug challenge, with 10/11 symptomatic patients having a
spontaneous type 1 ECG. In contrast to adult data, there was no male
preponderance in this population (again not unexpected, as one would
expect the sex hormones to have an unimportant role in this
predominantly pre-pubertal population), and supraventricular
arrhythmias were quite common. Episodes of syncope or SCD were also
commonly associated with fever, emphasising the importance of rapid
antipyretic therapy in this population. It has been shown in several
studies that there are temperature-dependent modifications in sodium
channel properties, which may underly the propensity for atrial or
ventricular arrhythmias; the reason why this is particularly so in
children is as yet unclear [65,66]. Brugada syndrome was also present
in at least 1 family member in 25/30 (83%) of children (including a
family history of sudden death in 10/25 children). However, a family
history of sudden death did not predict an adverse outcome, with the
majority of children with a family history of SCD being asymptomatic at
the time of assessment. Being a highly selected population, there was,
not unexpectedly, also a high incidence of SCN5A mutations. Apart from
the association of potentially life-threatening events with fever, the
study also suggested that quinidine might be effective in preventing
potentially lethal arrhythmias in children, and might even be
considered as a bridge to eventual ICD implantation.

Risk
stratification in children with Brugada syndrome

Provocative testing

While drug testing may help to establish the diagnosis of Brugada
syndrome, there are no data to show that a positive drug test alone,
using either ajmaline or flecainide correlates with symptoms or with
risk of sudden death. Exercise testing plays no role in risk
stratification, as the majority of syncopal or sudden death events
occur at rest. The role of invasive EP study is similarly
controversial. Based on meta-analyses of large adult studies, the role
of routine EP testing for the purpose of risk stratification has
generally been abandoned. It is however as yet unclear (apart from the
possibility of a selection bias towards more severe cases in the series
reported by the Brugada brothers) why there is such a discrepancy
between their data and other studies [67-70]. There is general
consensus that a negative EP study has a good negative predictive
value, particularly in previously asymptomatic individuals [67]. The
majority of asymptomatic individuals with a negative EP study
(non-inducibility of ventricular arrhythmia) remain asymptomatic at
follow-up. We have largely abandoned invasive EP studies in young
children with a positive family history of Brugada syndrome, as these
have invariably been negative. Our standard EP protocol for these
patients has been to pace from 2 right ventricular sites, with upto 3
extrastimuli with a minimum coupling interval of 200ms; it may be
argued that this protocol is not aggressive enough, and that
stimulation of epicardial sites also needs to be considered. To date
however, we have had no inducible VT using this protocol, and none of
the children has died suddenly or had a documented ventricular
arrhythmia at follow-up. At present, we are implanting loop recorders
(ILRs) in patients with a positive family history (where a family
member has either died suddenly or has an ICD) who present with
unexplained syncope. Despite this approach, we have not identified any
child with ventricular arrhythmias documented by the ILR, where syncope
was the presenting complaint. This suggests that syncope is common in
the young population, and is in the majority of children unrelated to
potentially lethal tachyarrhythmias.

Genetic testing

The cardiac sodium channel is the main determinant of impulse formation
and propagation in the heart, and loss of function SCN5A mutations,
with consequent slowing of cardiac conduction velocities result in the
Brugada syndrome [71]. Other rare mutations involving the genes
encoding subunits of the L-type calcium channel may also result in this
clinical phenotype [72]. Currently, more than 100 mutations in 7
different genes have been associated with the Brugada syndrome [73].
Genotype-phenotype correlations in the Brugada syndrome have been less
well investigated because only approximately 30% of patients with the
clinical phenotype have a positive genotype, suggesting the possibility
of genetic heterogeneity. It is recognised however that patients with
established SCN5A mutations may have a higher incidence of resting ECG
abnormalities and a larger increase in QRS duration following the
administration of sodium channel blockers [74]. The PQ and QRS
intervals in lead V2 were also more markedly prolonged with aging in
the SCN5A mutation-positive group during follow-up [75]. Histological
studies also showed significant apoptosis in the ventricular myocardium
in patients with SCN5A mutations, suggesting further that abnormal
sodium channel function may result in cellular damage, and an increased
risk for arrhythmic events [76]. More recently, there has been
preliminary evidence to suggest that the type of SCN5A mutation
(missense mutations M - in which a single amino acid is replaced
by an aberrant one versus premature truncations - T mutations -
where the sodum channel protein is truncated because of the presence of
a premature stop codon) and the degree of reduction in INa may have an
effect on the phenotype [77]. The proportion of patients who
experienced syncope (presumed to be arrhythmic in origin) was higher in
those with a T mutation than those with an M mutation, as was the
proportion of families in whom SCD had occurred in a first degree
family member at a young age. Even among the M mutations, the clinical
phenotype was more severe in patients with more severe INa reduction (M
mutations with >90% peak INa reduction versus M mutations with ≤90%
INa reduction). Further evidence of the potential clinical
importance of genotyping is provided by the knowledge that specific
SCN5A mutations are associated with a high risk of sudden death in
selected populations [78]. Certain ethnic-specific gene polymorphisms
may also affect the clinical expression of the disease, although it is
at present unlikely that this information can be incorporated into
clinical practice [79,80].

Clinical risk stratification

The presence of a spontaneous type 1 ECG (usually recorded in the
context of symptoms such as syncope or aborted cardiac arrest in the
individual, or when the patient presents for routine screening with a
positive family history of Brugada syndrome) appears to be the only
reliable marker for possible adverse arrhythmic events. As the ECG can
vary on a daily basis, it is important therefore to undertake routine
clinical follow-up, and obtain 12 lead ECG recordings every 6 months in
asymptomatic individuals. Where a type 1 ECG occurs in combination with
symptoms the treatment pathways become clearer; ACA=ICD;
syncope=quinidine ± ILR ± ICD. What to do in the presence
of a spontaneous type 1 ECG in an asymptomatic individual is
controversial. Adult studies have shown that there is a near-equal
distribution of a type 1 ECG between symptomatic and asymptomatic
subjects [57,59]. Further developments in our understanding of the
genetics of the disease may help in risk stratification. In selected
patients with adverse family histories, prophylactic oral quinidine
therapy may be considered [81,82]. It is also important in such
patients to avoid drugs that have been reported to induce the type 1
ECG and/or fatal arrhythmias. A list of these, and current
recommendations concerning their use, may be found at
www.BrugadaDrugs.org [83]. A variety of additional ECG markers have
been identified, which are associated with an increased risk of
ventricular arrhythmias. These include daily fluctuations in the
standard and signal averaged ECGs [84], prolonged QRS interval in V6 of
≥ 90ms and prolonged r-J interval in V2 of ≥ 90ms [85]), fragmented QRS
complexes [86,87], late potentials on signal-averaged ECGs [88,89],
spontaneous changes in ST segments on continuous or multiple ECG
recordings [90], and increased Tpeak-Tend duration and Tpeak-Tend
dispersion [91]. The clinical utility of these parameters in general
practice remains to be established.

Data from adult patients in whom ICDs have been implanted confirm that
there is a low incidence of arrhythmic events at follow-up [92]. There
is also a significant risk of device-related complications
(approximately 9% per year), and it has been reconfirmed that recurrent
syncope can occur in this population also in the absence of arrhythmia.
In contrast to previous studies which suggested a good negative
predictive value for EP studies, ICD follow-up data also show that the
EP study may be limited even in this predictive function. The ICD
however is protective, and none of the patients with an ICD died during
follow-up [92].

Catecholaminergic polymorphic
ventricular tachycardia (CPVT)

Genetic aspects

Familial forms account for between 30 and 50% of CPVT, with both
autosomal dominant and recessive forms having been recognised (dominant
ryanodine RyR2 receptor gene defect – CPVT1 - and recessive
calsequestrin 2 –CPVT2 - gene defects) [93,94]. The RyR2-encoded
ryanodine receptor gene, mutations of which cause CPVT type 1 (CPVT1)
is a relatively large gene, with mutations having been identified in up
to 45 of of the 105 translated exons. Despite this large gene size, up
to 65% of CPVT1-positive mutations can be discovered by selective
analysis of 16 exons, which makes a tiered approach to genetic
diagnosis feasible [95].

Clinical
presentation

The syndrome has its clinical onset at a young age, and is
characterised by ventricular arrhythmias occurring during exercise,
typically when the heart rate exceeds a threshold value of between 120
and 130/minute [96]. The initial presentation may be syncope, epileptic
seizures secondary to ventricular arrhythmia and cerebral hypoxemia
(which are often misdiagnosed as primary epileptic seizures), or sudden
death. The disease is associated with a high mortality, with 30 to 35%
of patients with the clinical disease dying before the age of 30 years.
There is also often a strong family history of syncope or sudden death,
occurring in upto 30% of patients [96]. Akin to LQTS1, ventricular
arrhythmias may also be triggered during swimming, and CPVT1 causing
RyR2 mutations were identified in up to 90% of patients with
swimming-triggered arrhythmic events who were lacking sufficient
clinical evidence for the diagnosis of LQTS [97]. RyR2 gene mutations
have been identified at post-mortem in young individuals dying suddenly
and unexpectedly [98,99] even when death occurred at rest, and may
also be causal in a small proportion of sudden infant death syndrome
[100]. This emphasises the importance of obtaining a genetic diagnosis
where possible even after death, so that surviving relatives may be
appropriately investigated and treated [101].

Risk
stratification

The resting ECG is normal, and invasive EP studies have no
role.
Diagnosis, risk stratification and therapy are all guided by the
clinical presentation in the individual, and by the family history
(sudden unexplained death in a first degree relative, or established
diagnosis in a family member). Therapy consists of avoidance of
exercise and beta blocker therapy. The response to beta-blockers is
variable, and additional measures are often necessary [102,103]. In
patients with persistent symptoms additional therapeutic approaches
include the addition of a calcium channel blocker [104], selective left
sided cardiac sympathetic denervation [105,106] and/or implantation of
an ICD [107,108].